Effect of Acupuncture vs Sham Acupuncture on Patients With Poststroke Motor Aphasia

Key Points Question What is the efficacy of acupuncture combined with language training in the treatment of motor aphasia in patients with stroke? Findings In this randomized clinical trial involving 252 patients in China with poststroke motor aphasia, those who received 6 weeks of acupuncture treatment with up to 6 months of follow-up showed significant improvements in language function, quality of life, and neurological impairment compared with those who received sham acupuncture. Meaning These findings suggest that acupuncture can greatly improve language function in patients with poststroke motor aphasia.

group will receive sham acupuncture therapy.Both groups will receive language training and conventional treatment, with a follow-up for up to six months post-onset.

Background
Poststroke motor aphasia is a common complication of ischemic stroke that leads to harmful effects in patients and is a significant economic burden on society 1 .Aphasia has been reported in approximately 21%-38% of acute ischemic stroke patients [1][2][3] .
Acupuncture has been used in China for thousands of years as a form of Traditional Chinese Medicine therapy.It is effective in treating poststroke motor aphasia by improving functional communication and language function 4,5 .Some studies have revealed the effects of acupuncture on spontaneous speech, repetition, naming, and communication ability in patients with poststroke motor aphasia 6,7 .However, high-quality evidence based on well designed, sham-controlled, large-sample size randomized clinical study are needed to further prove the effects of acupuncture on poststroke motor aphasia 6,8,9 .
Currently, multiple approaches have shown the therapeutic effects on improving poststroke aphasia.For the pharmacotherapy, studies have demonstrated the beneficial impact of medication combined with behavioral therapy 10 .However, the effectiveness of pharmacotherapy on poststroke aphasia lacks robust evidence 11 .Behavioral approaches such as speech and language therapy (SLT) or neuropsychological treatment indicate the improvement on communication ability 12 .It has been proved that language training improved oral naming accuracy for trained items in patients with aphasia, with long-term gain maintenance over time 13 .Thus, SLT may be beneficial at high intensity, at a high dose, or over a longer period 14 .
The main objectives of this trial are to evaluate the efficacy and safety of acupuncture for ischemic stroke patients with poststroke motor aphasia from 15 to 90 days after the onset of aphasia.

Study Hypothesis
Acupuncture is an effective approach for treating poststroke motor aphasia, and its efficacy is superior to that of sham-acupoint acupuncture.

Trial Design
This is a multicenter randomized sham-controlled clinical trial.A total of 252 participants will be randomized into manual acupuncture (MA) or sham acupuncture (SA) groups at a 1:1 ratio.Each eligible subject will undergo a 6-week treatment period, with follow-up at the end of 6 weeks of treatment and 6 months after onset.In total, six visits are scheduled for each subject at weeks 0, 2, 4, 6, and 12 and at 6 months after onset.(Table 1, Figure 1) Figure 1.Study design and participation flow chart

Randomization and Concealment
The China Academy of Chinese Medical Sciences was commissioned to apply the "Central Randomization System for Clinical Research."The 252 participants will be randomly assigned to the experimental and control groups at a 1:1 ratio using the district-group randomization method.
The central randomization system was established to implement the allocation sequence and conceal the sequence until interventions are assigned.Throughout the study, Central will perform randomization and maintain the list, and statisticians will be continuously blinded to data management until the database is closed.

Blinding
Trial participants, outcome assessors, and statistical analysts will be blinded after being assigned to the intervention.Trial participants will be randomly assigned.The outcome assessor will enter the measurements into the computer, and the statistical analyst will analyze the data without access to the assignment information.The data will be reviewed in a blinded manner, entrusting third-party (Guangdong Provincial Hospital of Chinese Medicine) medical statistics professionals to conduct the statistical analysis.

Sample Size
Based on a previous pilot study, we expected that acupuncture combined with speech rehabilitation would be more effective than placebo combined with speech rehabilitation 6 .We assumed that the difference in the Western Aphasia Battery (WAB)-aphasia quotient (AQ) values after treatment between acupuncture and placebo was 10.9, with a standard deviation of 22.9 in both groups.
According to expert clinical observations, a superiority margin of 3 was found for comparisons between acupuncture and placebo for the primary outcome.We performed a superiority test to calculate the appropriate trial sample size with 80% power, β= 0.2, and α= 0.05.The results showed that a clinically significant difference could be detected with a sample size of at least 105 participants in each group, allowing for a predicted 20% dropout rate.We plan to enroll 252 participants in this study.

Subjects
Patient data will be collected throughout the clinical trials in China at three tertiary hospitals in Tianjin, Changchun, and Jinan.

Inclusion Criteria
(I) Patients diagnosed with ischemic stroke according to the International Classification of Diseases code ICD-10-I63.902 15 .
(II) Patients diagnosed with aphasia for the first time after stroke.
(III) Patients diagnosed with aphasia ranging from 15 to 90 days after onset.
(IV) An aphasia severity of 0-3 that can cooperate with speech training.
(V) Consciousness and stable vital signs.
(VI) Patients aged 45-75 years and either male or female.
(VII) Patients and their families understand the research content fully, agree to participate, and signed the informed consent form.

Exclusion Criteria
(I) Patients diagnosed with aphasia not caused by stroke.
(II) Patients with aphasia occurring before stroke onset.
(III) Patients with severe heart disease and kidney and liver function insufficiency.
(IV) Patients with audiovisual dysfunction, severe cognitive impairment, or mental illness who cannot cooperate with examination and treatment.
(V) Pregnant or lactating women.

Dropout criteria
(I) Patients with poor compliance during the clinical study who are unwilling to accept the intervention or who withdraw voluntarily.
(II) Patients who experience severe adverse reactions or deterioration during the clinical study and are not eligible for further intervention.

Subject recruitment and informed consent acquirement
The study will be conducted at the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Changchun University of Chinese Medicine, and Qilu Hospital of Shandong University.
Participants diagnosed with ischemic stroke with aphasia will be recruited at three hospitals, mainly from clinical processes.Additionally, we will recruit participants through posters and flyers.Participant screening will be completed at each center by experienced researchers.Informed consent will be obtained from eligible patients, and then they will be randomized into groups.

4.1
Before the start of clinical studies, trained researchers will discuss the trial with the participants, including the research nature, research purpose, and possible benefits and dangers, thereby meeting the requirements of the Declaration of Helsinki and the rights and obligations of the participants.Patients will be able toparticipant in informed discussions with the researchers.The participants or their legal representatives will understand, agree to, and sign a written informed consent form indicating their willingness to participate in the trial.

Primary Outcome
The main observation will be the difference between the two groups in the AQ of the WAB and the Chinese Functional Communication Profile (CFCP) score after 6 weeks of treatment.
(I) The AQ reflects the language ability of patients with aphasia according to the Research Outcome Measurement in Aphasia consensus statement recommendation 16 .A lower AQ score indicates more severe impairment of language function.Patients will be asked to answer questions about word recognition, repetition, sentence comprehension, and oral expression.Assessment time frames: at baseline; at weeks 2, 4, 6, and 12; and 6 months after onset.
(II) The CFCP represents the functional communication ability of the Mandarin language of which a higher score is related to better ability.The evaluator will ask the patients questions to assess their communication ability 17 .Assessment time frames: at baseline; at weeks 2, 4, 6, and 12; and 6 months after onset.

Secondary Outcomes
(I) Boston Diagnostic Aphasia Examination (BDAE) grading.The BDAE grade indicates the severity of the language competence status, and grades 0-5 reflect communication capacity from nonsense to full capacity.Evaluators will assess the severity of language impairment according to the patient's comprehensive condition.Assessment time frames: at baseline; at weeks 2, 4, 6, and 12; and 6 months after onset.
(II) Stroke and Aphasia Quality of Life Scale-39 (SAQOL-39) 18 score.The SAQOL-39 assesses the physical, psychological, and communication conditions in the daily lives of patients with aphasia.
Participants will be asked to answer questions regarding different aspects.Assessment time frames: at baseline; at weeks 2, 4, 6, and 12; and 6 months after onset.
(III) Stroke-Specific Quality of Life Scale (SS-QOL) scores 19 .The SSQOL evaluates the activity of daily living in patients with stroke.Evaluators will ask questions to judge their quality of life.
(IV) National Institutes of Health Stroke Scale (NIHSS) 20 scores.The NIHSS score reflects the neurological deficits associated with stroke.Evaluators will observe participants' physical activity and ask them to follow instructions to evaluate their condition.Assessment time frames: at baseline; at weeks 2, 4, 6, and 12; and 6 months after onset.
(V) Health Scale of Traditional Chinese Medicine (HSTCM) 21 scores.HSTCM reveals the comprehensive health condition based on the Chinese medicine theory system.Evaluators will ask questions to judge the participants' comprehensive condition.Assessment time frames: at baseline; at weeks 2, 4, 6, and 12; and 6 months after onset.

Adverse events
Adverse reactions/events will be recorded in detail, including the time of occurrence of adverse events, symptoms and signs, laboratory examination results, treatment to relieve adverse events, follow-up of adverse events, duration and severity of adverse events, and the combination of pharmaceutical therapy.
For any serious adverse event occurring during the study (including events requiring hospitalization or prolonged hospitalization; events causing disability or impact on work ability, life-threatening events or death, etc.), during the clinical trial, the investigator must take appropriate treatment measures immediately and report to the ethics committee within 24 hours or no later than the second working day.

Explanation for the choice of comparators
Sham acupuncture therapy is commonly used and recommended by international experts as a control in acupuncture-related randomized clinical trials.Manipulators will choose acupoints that are 1 cun away from the acupoints of the manual acupuncture group.The stimulating amount of acupuncture requires no "De Qi" sensation.Sham-acupoint acupuncture mainly involves sham acupoints that are not located on the meridians and have no therapeutic effect on aphasia.

Intervention description
To ensure consistency in interventions, qualified acupuncturists with certifications will be selected and trained on the location of acupuncture points, depth, direction of insertion, and frequency of lifting and inserting.Speech therapists will receive training related to the study prior to recruitment and speech training techniques.All acupoints will be localized according to the World Health Organization (WHO) standards.Disposable sterile acupuncture needles (0.25 mm × 40 mm, 0.25 mm × 75 mm; Hwato brand; Suzhou Medical Supplies Factory Co. LTD, Suzhou, China) will be used.Subjects in the experimental group will receive manual acupuncture, and those in the control group will receive sham acupoint acupuncture.Additionally, language training for aphasia and conventional treatment for ischemic stroke will be allowed, which are included in the Guidelines for the Diagnosis and Treatment of Integrated Traditional Chinese and Western Medicine in Cerebral Infarction in China (2017) 22 .The same acupuncturist in each clinical center will perform acupuncture treatment for participants in both the MA and SA groups, and the same language trainer will deliver language training for participants in both groups.

Manual acupuncture group
"Xing-Nao Kai-Qiao" acupuncture therapy will be applied to treat poststroke motor aphasia according to traditional Chinese theory.The acupoints include bilateral PC6 (Neiguan), GV26 (Shuigou), bilateral side SP6 (Sanyinjiao), and CV23 (Lianquan), and beside CV23 (left Panglianquan and right Panglianquan), affected side HT1 (Jiquan), affected side LU5 (Chize), and affected side BL40 (Weizhong).Acupoints PC6 and GV26 are inserted at a depth of 5-10 mm, acupoint CV23 is inserted at a depth of 55 mm, and the others are inserted at a depth of 25-35 mm.After penetration, lifting-pushing and spinning-rotating manipulations will be performed to achieve the "De Qi" sensation.The acupoint location, needle method, acupuncture manipulation, and "De Qi" responses are shown in Table 2.
Finally, after 30 min of retention, all needles are removed.Participants will receive treatment 5 times a week for 6 consecutive weeks.

Sham acupuncture group
Sham-acupoint acupuncture mainly involves sham acupoints that are not located on the meridians and have no therapeutic effect on aphasia.We elected the acupoints to be studied according to the WHO international standards for acupoint selection.Additionally, with the manual acupoints as a reference, the lateral opening of about 1 cun in the horizontal direction at selected nonmeridian and nonacupoint will serve as sham acupoints.The stimulating amount of sham acupuncture requires no "De Qi" sensation.The same procedure will be used as that for the MA group.The sham acupoint location, needle method, acupuncture manipulation, and "De Qi" responses in the SA group are shown in Table 2.
to analyze changes in measurements at different time points.Covariates such as age, duration of illness, and severity of aphasia will be included in the statistical model to correcting for the effects of possible imbalances.If the distribution assumption is violated, and appropriate transformation will be used.Data analysis will be performed based on the intention-to-treat analysis (ITT) and per-protocol analysis (PP) principles.Missing outcome data will be replaced using the last observation carried forward (LOCF) or multiple imputation method.We will also assess the robustness of the results of our research by comparing the results of the two datasets mentioned above to evaluate group effects.

Ethics and dissemination
This study was approved by the ethics committee of the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine and is registered on ChiCTR with the ID ChiCTR1900026740.
Informed consent will be obtained from all included participants before randomization.The results of this trial will be published in a peer-reviewed academic journal.

Ethical Approvals of all participating hospitals
This trial will be conducted at three hospitals.The ethical review was firstly submitted to the ethics committee of the principal organization, the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, and then to the ethics committees of the other participating hospitals.This trial was approved by all of the ethics committees.Ethical approvals are attached as follows. 1 the face, at the intersection of the upper one-third and middle one-third of the philtrum midline Insert at a depth of 5the volar aspect of the forearm, at the junction of Quze (PC3) and Daling (PC7), 2 cun above the wrist crease in the space between tendon palmaris longus and vagina tendinis musculi flexoris carpi radialis Insert at a depth of 5-10 mm Counterclockwise at the left side and clockwise at the right side with twisting force, together with light insertion and heavy lifting, region of the neck, superior to the superior border of the thyroid cartilage, in the depression superior to the hyoid bone on the anterior median line Insert at a depth of 55 mm Light insertion and heavy lifting In the axilla, in the center of the axillary fossa, over the axilary artery Insert at a depth of 25-35 mm Light insertion and heavy lifting manipulation Make the affected arm twitch three times.Chize (LU5) In the cubital crease, at the depression of the bicipital muscle tendon radialis at the elbow Insert at a depth of 25-35 mm Light insertion crus inside, 3 cun above the upper border of the medial malleolus of the ankle at the posterior border of the tibia Insert at a depth of 25-35 mm Heavy insertion and light lifting manipulation aspect of the forearm, 2 cun above the wrist crease, between the flexor carpi radialis tendon and brachioradialis tendon Insert needle in 0.2 cun Without needle manipulation Deep ache or dull ache, without spreading Sham GV26 On the face, by the sides of GV26 1cun, above the corner of the mouth Insert needle toward the nasal septum in 0.2 cun Sham SP6 In crus inside, 3 cun above the tip of the medial malleolus, at the anterior border of the tibia, about 1.25 cun in front of SP6 Insert needle along with the medial border of the tibia in 0.2 cun Sham HT1 Extend the upper arm, 1 cun below the apex of the armpit, about 1 cun forward, avoiding the armpit hair, over the abdomen of the biceps Insert needle in 0.2 cun Sham LU5 Bend the elbow 120°, at the midpoint of the line between LU5 and LI11 Insert needle in 0.2 cun Sham BL40 On the belly of peroneus longus, at the inferolateral of BL40.Inferior to BL40 1cun and lateral to 1cun Insert needle in 0.2 cun Sham CV23 At the rear of CV23, and by the sides of the median line 1cun Insert needle in 0.2 cun Sham beside CV23 At the rear of beside CV23, and by the sides of the median line 2cun Insert needle in 0.2 cun a cun: 1 cun (≈25 mm) is defined as the width of the interphalangeal joint of the patient's thumb.
Sponsors and researchers are requested to conduct the clinical study in strict compliance with the Good Clinical Practice regulations and the protocol approved by this Ethics Committee (Version 1, Date: 20190627), Informed Consent Form (Version 1, Date: 20190627).Clinical trial registration (including registration in the Medical Research Registration and Filing Information System) must be completed prior to the commencement of the study.If any of the following occurs during the project, a written report should be submitted to the ethical committee: (1) any modification to the clinical protocol, informed consent, etc.; (2) replacement of the principal investigator; (3) occurrence of serious adverse events; (4) occurrence of any situation that may affect the conduct of the trial or increase the risk to the subjects; (5) violation of the protocol; (6) suspension or early termination of the clinical study.The Ethics Committee will follow up on this project with a frequency of 12 months.Please submit a progress report by July 27, 2020.Upon completion of the project, please submit a final report.This approval is valid from August 27, 2019 to August 27, 2022.IEC of The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine Date: Aug 27, 2019 This approval is valid for 2 years from the date of issuance, and the researcher must strictly use the text of the informed consent form and the research protocol approved by the ethical committee.If the clinical studies (including statistical analyses) cannot be completed at the time of expiration of the ethical approval, please submit a request for a follow-up review one month before the expiration of the approval.Please submit the follow-up application 1 month before July 20, 2021.If the study is completed and within the validity period of the approval, a final report should be submitted to the Ethics Committee.Suspension or early termination of the clinical study should be notified to the Ethics Committee timely.Serious adverse events and unintended adverse events affecting the risk-benefit ratio of the study should be reported to the Ethics Committee.Any modification of the clinical research protocol and informed consent form, including the change of principal investigator, etc., should be submitted to the Ethics Committee for re-examination and approval before implementation.Protocol violations that affect subjects' willingness to participate in the study should be reported promptly.Hospital of Shandong University 363

Table 1 .
Schedule of enrollment, interventions, and assessments.
. First Teaching Hospital of Tianjin University of Traditional Chinese Medicine issued by Council for International Organizations of Medical Sciences.After review by the Ethics Committee of the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine on August 27, 2019, the project "A randomized controlled trial for 'Xing-Nao Kai-Qiao' Rehabilitation Program in the Treatment of Motor Aphasia after Stroke" was approved by the ethical committee of the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, and the project investigator, Zhihong Meng, should be responsible for the clinical research project.